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Relevance of temozolomide for elderly patients with MGMT promoter-methylated malignant astrocytomas outside the RTK I methylation group [HD collective]

ABSTRACT: Relevance of temozolomide for elderly patients with MGMT promoter-methylated malignant astrocytomas outside the RTK I methylation group [HD collective]

PROVIDER: PRJNA507175 | ENA |

REPOSITORIES: ENA

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Relevance of temozolomide for elderly patients with MGMT promoter-methylated malignant astrocytomas outside the RTK I methylation group

Project description:Relevance of temozolomide for elderly patients with MGMT promoter-methylated malignant astrocytomas outside the RTK I methylation group

| PRJNA506921 | ENA

Relevance of temozolomide for elderly patients with MGMT promoter-methylated malignant astrocytomas outside the RTK I methylation group [HD collective]

Project description:The data contains Illumina 450k/EPIC array methylation files from 380 glioblastoma patients of the Heidelberg Neuro-Oncology Center

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Relevance of temozolomide for elderly patients with MGMT promoter-methylated malignant astrocytomas outside the RTK I methylation group

Project description:The data contains Illumina 450k/EPIC array methylation files from 104 patients of the NOA-08 study comparing temozolomide alone vs. radiotherapy in elderly patients with glioblastoma

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DNA methylation analysis of paediatric pilocytic and diffuse astrocytomas

Project description:Paediatric low-grade gliomas (LGGs) account for about a third of all brain tumours in children. We conducted a detailed study of DNA methylation to improve our understanding of the biology of pilocytic and diffuse astrocytomas. Comparisons were performed between tumours and normal brain controls from matching location, and between pilocytic and diffuse astrocytomas. Pilocytic astrocytomas were found to have a distinctive signature involving 315 CpG sites, with the majority of the sites (312 CpG sites) hypomethylated in pilocytic astrocytomas. Additionally many of the sites were located within annotated enhancers. The distinct signature in pilocytic astrocytomas was not present in diffuse astrocytomas or in published profiles of other brain tumours and normal brain tissue. On further analysis of the 315 CpG sites, the AP-1 transcription factor complex was predicted to bind within 200bp of a subset of teh 315 differentially methylated CpG sites. We also observed up-regulation of the AP-1 factors, FOS and FOSL1 in pilocytic astrocytomas. Our findings highlight novel epigenetic differences between pilocytic and diffuse astrocytomas, in addition to well-described alterations involving BRAF, MYB and FGFR1.

2016-05-10 | GSE77241 | GEO

A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma

Project description:Temozolomide (TMZ) has been used for the treatment of glioblastoma (GBM) since last decade, but its treatment benefits are limited by acquired resistance, a process that remains incompletely understood. Here we report that a novel enhancer, located between the promoters of Ki67 and O6-methylguanine-DNA-methyltransferase (MGMT) genes, is activated in TMZ-resistant patient-derived xenograft (PDX) lines as well as in recurrent tumor samples. Activation of the enhancer correlates with increased MGMT expression, a major known mechanism for TMZ resistance. We show that forced activation of the enhancer in cell lines with low MGMT expression results in elevated MGMT expression. Deletion of this enhancer in cell lines with high MGMT expression leads to reduced levels of MGMT and Ki67, increased TMZ sensitivity and impaired proliferation. Together, these studies uncover a novel mechanism that regulates MGMT expression, confers TMZ resistance and potentially regulates tumor proliferation.

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Gene Expression Profiling of Human Pediatric Astrocytomas

Project description:Analysis of grades II, II and iV pediatric astrocytomas. Results used to straify tumors into molecular subclasses representative of adult tumors. The mesenchymal subtype is associated with high expression of immune response-related genes. Gene expression of grade II, III and IV pediatric astrocytomas, 24 individual tumor samples were profiled

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Array-CGH screening of pediatric low-grade astrocytomas (n=66)

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Capicua controls Toll/IL-1 signaling targets independently of RTK regulation

Project description:The HMG-box protein Capicua (Cic) is a conserved transcriptional repressor that functions downstream of receptor tyrosine kinase (RTK) signaling pathways in a relatively simple switch: in the absence of signaling, Cic represses RTK-responsive genes by binding to nearly invariant sites in DNA, whereas activation of RTK signaling downregulates Cic activity, leading to derepression of its targets. This mechanism controls gene expression in both Drosophila and mammals, but whether Cic can also function via other regulatory mechanisms remains unknown. Here we characterize an RTK-independent role of Cic in regulating spatially restricted expression of Toll/IL-1 signaling targets in Drosophila embryogenesis. We show that Cic represses those targets by binding to suboptimal DNA sites of lower affinity than its known consensus sites. This binding depends on Dorsal/NF-kB, which translocates into the nucleus upon Toll activation and binds next to the Cic sites. As a result, Cic binds to and represses Toll targets only in regions with nuclear Dorsal. These results reveal a new mode of Cic regulation unrelated to the well-established RTK-Cic depression axis and implicate cooperative binding in conjunction with low-affinity binding sites as an important mechanism of enhancer regulation. Given that Cic plays a role in many developmental and pathological processes in mammals, our results raise the possibility that some of these Cic functions are independent of RTK regulation and may depend on cofactor-assisted DNA binding.

2018-01-05 | GSE104839 | GEO

CpG island hypermethylation in human astrocytomas

Project description:Astrocytomas are common and lethal human brain tumors. Here, we have analyzed the methylation status of over 28,000 CpG islands and 18,000 promoters in normal human brain and in astrocytomas of various grades using the methylated-CpG island recovery assay (MIRA). We identified six to seven thousand methylated CpG islands in normal human brain. ~5% of the promoter-associated CpG islands in normal brain are methylated. Promoter CpG island methylation is inversely and intragenic methylation is directly correlated with gene expression levels in brain tissue. In astrocytomas, several hundred CpG islands undergo specific hypermethylation relative to normal brain with 428 methylation peaks common to more than 25% of the tumors. Genes involved in brain development and neuronal differentiation, such as POU4F3, GDNF, OTX2, NEFM, CNTN4, OTP, SIM1, FYN, EN1, CHAT, GSX2, NKX6-1, RAX, PAX6, DLX2, were strongly enriched among genes frequently methylated in tumors. There was an overrepresentation of homeobox genes and 31% of the most commonly methylated genes represent targets of the Polycomb complex. We identified several chromosomal loci in which many (sometimes more than 20) consecutive CpG islands were hypermethylated in tumors. Seven of such loci were near homeobox genes, including the HOXC and HOXD clusters, and the BARHL2, DLX1, and PITX2 genes. Two other clusters of hypermethylated islands were at sequences of recent gene duplication events. Our analysis offers mechanistic insights into brain neoplasia suggesting that methylation of genes involved in neuronal differentiation, perhaps in cooperation with other oncogenic events, may shift the balance from regulated differentiation towards gliomagenesis. Comparison of methylation patterns of 30 astrocytomas and 6 controls

2010-05-16 | E-GEOD-19391 | biostudies-arrayexpress

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